Project Summary/Abstract It is becoming clear that CD4 T cell plasticity is an important aspect of initiating and regulating immune responses. Among the factors that play a critical role in determining T cell differentiative fate is TGF. Recent work has shown that TGF, through its ability to induce the expression of both Foxp3 and RORt, is involved in iTreg/Th17 differentiation. Exposure of CD4 T cells to antigen in the presence of TGF alone leads to iTreg development, while the presence of inflammation cytokines (e.g., IL-6) with TGF results in Th17 differentiation. Thus, the ability of TGF to regulate the expression of Foxp3 and RORt based on microenvironmental cues, is a key aspect of T cell function. Factors that regulate TGF function are therefore important players in this process. One such factor is the proto-oncogene c-Ski. The Ski gene was first identified as v-Ski, the retroviral oncogene in Sloan-Kettering retroviruses capable of transforming chicken embryo fibroblasts. The cellular homolog, c-Ski, has been shown to be important for several aspects of embryonic development, and Ski- deficiency leads to late embryonic death. Ski functions as a natural inhibitor of the TGF signaling pathway by targeting several downstream signaling events. However, a role for Ski in the immune system has not been determined. Given the important role of TGF in regulating immune responses, a better understanding of Ski in the context of immune development and responses is important. For this work we have generated a mouse strain that contains a conditional knockout allele of Ski, allowing us to delete Ski specifically in T cells. These mice will allow us to determine the role of Ski in T cell homeostasis and function. With this in mind, the aims of this proposal are: 1. Determine the role of Ski in regulating TGF-mediated effects in CD4 T cells; 2. Determine the role of Ski in regulating T cell homeostasis; 3. Determine the effect of Ski-deficiency on CD4 T cell function.